Pregabalin, or (S)-3-(aminomethyl)-5-methylhexanoic acid, binds to the calcium channel alpha-2-delta (α2δ) subunit and is related to endogenous inhibitory neurotransmitter gamma-amino butyric acid (GABA), which is involved in brain neuronal activity. In the United States, pregabalin has been approved for the management of neuropathic pain associated with diabetic peripheral neuropathy, management of post herpetic neuralgia, management of fibromyalgia, and as an adjunctive therapy for adult patients with partial onset seizures.
Pregabalin is disclosed in U.S. Pat. Nos. 6,197,819 and 5,563,175, which describe its use in the treatment of seizure disorders. U.S. Pat. No. 6,117,906 discloses the use of pregabalin in treating anxiety, while U.S. Pat. No. 6,001,876 discloses its use in treating pain.
Currently, pregabalin is available as conventional immediate-release capsules marketed by CP Pharms/Pfizer under the brand name Lyrica®, Lyrica® requires two or three times a day dosing. The importance of taking drugs at regular intervals cannot be overemphasized. However, it is not easy for everyone to remember to take the correct dose at the same time each day. Multiple dosing is not only inconvenient but it also lowers patient compliance. Once daily dosing generally improves patient compliance as well as reduces the severity and frequency of side effects by reducing peak blood levels and may also increase drug efficacy by increasing minimum plasma concentration. Once daily dosing of pregabalin, however, presents numerous challenges. Conventional extended-release compositions are problematic as pregabalin does not have uniform absorption throughout the entire gastrointestinal tract. Pregabalin is absorbed well in the small intestine and the ascending colon, but is poorly absorbed beyond the hepatic flexure. This suggests that the mean absorption window for pregabalin is, on average, about six hours or less and any drug-release from a conventional extended-release dosage form beyond six hours would thus be wasted because the dosage form has travelled beyond the hepatic flexure.
U.S. Publication Application No. 2007/0269511 discloses a pregabalin formulation containing matrix forming agent and a swelling agent wherein the matrix forming agent is polyvinyl acetate and polyvinylpyrrolidone, and the swelling agent is cross-linked polyvinylpyrrolidone. U.S. Publication Application No. 2011/0135723 describes once-daily pharmaceutical compositions of pregabalin wherein the excipients include one or more water-insoluble components, or a combination of one or more water-insoluble components and one or more water-soluble components. U.S. Publication Application No. 2010/0255067 describes pharmaceutical compositions comprising pregabalin, a hydrophobic release controlling agent, and other pharmaceutically acceptable excipients. PCT Publication No. WO 2011/151708 describes a gastroretentive dosage form comprising a GABA analog, at least one swelling agent, and at least one non-swelling release retardant.
Therefore, a sustained-release gastroretentive dosage form would be an ideal dosage form for drug candidates like pregabalin. The objective of the present invention is to develop a gastroretentive tablet of pregabalin that not only extends the release of pregabalin but also retains pregabalin in the upper parts of the gastrointestinal tract for a long period of time to overcome its decreased colonic absorption.